Monosodium Urate Crystal‐Induced Pyroptotic Cell Death in Neutrophil and Macrophage Facilitates the Pathological Progress of Gout

Monosodium urate (MSU) crystal deposition in joints can lead to the infiltration of neutrophils and macrophages, and their activation plays a critical role in the pathological progress of gout. However, the role of MSU crystal physicochemical properties in inducing cell death in neutrophil and macrophage is still unclear. In this study, MSU crystals of different sizes are synthesized to explore the role of pyroptosis in gout. It is demonstrated that MSU crystals induce size‐dependent pyroptotic cell death in bone marrow‐derived neutrophils (BMNs) and bone marrow‐derived macrophages (BMDMs) by triggering NLRP3 inflammasome‐dependent caspase‐1 activation and subsequent formation of N‐GSDMD. Furthermore, it is demonstrated that the size of MSU crystal also determines the formation of neutrophil extracellular traps (NETs) and aggregated neutrophil extracellular traps (aggNETs), which are promoted by the addition of interleukin‐1β (IL‐1β). Based on these mechanistic understandings, it is shown that N‐GSDMD oligomerization inhibitor, dimethyl fumarate (DMF), inhibits MSU crystal‐induced pyroptosis in BMNs and J774A.1 cells, and it further alleviates the acute inflammatory response in MSU crystals‐induced gout mice model. This study elucidates that MSU crystal‐induced pyroptosis in neutrophil and macrophage is critical for the pathological progress of gout, and provides a new therapeutic approach for the treatment of gout. The size of MSU crystals is critical for the pathological progress of gout by inducing GSDMD‐dependent pyroptosis in neutrophil and macrophage. Dimethyl fumarate (DMF) is demonstrated to inhibit pyroptosis by suppressing the formation of N‐GSDMD in vitro, and further alleviate the MSU crystals‐induced inflammatory responses in vivo.